October 2015 Edition Vol.11, Issue 10

Five Hits and a Dud: A Snapshot of the 2015 European Cancer Congress

Five Hits and a Dud:
A Snapshot of the 2015 European Cancer Congress (continued)

RCC: Take Two
 

Not to be outdone, Toni Choueiri, MD, Dana-Farber Cancer Institute took the stage immediately following Dr. Sharma’s presentation to report on his study, METEOR, conducted in patients with advanced RCC using the drug, cabozantinib.  

“I am very excited about the outcome of the study since the results may change the standard of care in patients with advanced kidney cancer who have received prior standard (anti-angiogenic) therapy,” said Dr. Choueiri.

Cabozantinib, a tyrosine kinase inhibitor already approved for use in metastatic medullary thyroid cancer, blocks the signaling of multiple pathways including, RET, MET, VEGFR, KIT, AXL, and FLT-3. These kinases are variously involved in oncogenesis, cell proliferation, and metastasis.

“Increased MET and AXL expression has been associated with poor prognosis, and resistance to VEGFR (SOC) inhibition,” explained Dr. Choueiri. “Resistance in these patients is a major challenge.”

In the phase III METEOR trial, cabozantinib, a small molecule drug, was compared with everolimus in second line treatment for a cohort of patients with advanced RCC who had previously failed standard of care (N=658).

Results for efficacy in this difficult-to-treat population were striking; the overall response rate was 21% for cabozantinib treatment vs 5% for everolimus; and the progression-free survival (PFS) was 7.4 months for cabozantinib vs 3.8 months for the comparator (for both: p<0.001) (Figure 2).

A sub-analysis showed an even greater response in patients who received sunitinib as prior treatment; the PFS was 7.4 months for cabozantinib vs 3.8 for everolimus (HR=0.41).  

Though the trial is ongoing, this interim analysis suggested a strong trend for improved overall survival.

“This is a great day for kidney cancer patients,” Dr. Choueiri said. "We now have two new drugs with two distinct mechanisms of action to choose from.”

The clinical challenge ahead is, of course, which do you pick? As yet, the data do not say.

RADIANT-4
 

Not everyone was beating up on everolimus: the RADIANT-4 trial managed to demonstrate the drug as having superior efficacy as compared with placebo in a cohort of patients with neuroendocrine tumors (NETs) of lung or gastrointestinal origin.

“Everolimus has previously shown activity in pancreatic NET and is approved as a standard treatment option in that setting,” said RADIANT-4 investigator, James Yao, MD, of the MD Anderson Cancer Center, explaining the rationale for using the drug. “Unfortunately, effective therapeutic options for patients with advanced, progressive, nonfunctional NET of lung or GI are very limited. In fact, there are no agents approved that have demonstrated activity in patients with lung NET.”

In this phase III study, RADIANT-4 randomized 302 patients with NETs in a 2:1 fashion, everolimus vs placebo. The most common tumor sites in this population were lung (30%), and ileum (24%). Patients were treated until disease progression or intolerable adverse events occurred.

Results for treatment with everolimus showed an improved PFS of 11.0 months vs 3.9 months for placebo (HR=0.48; p<0.0001). “This means a 52% reduction in the relative risk of progression or death with everolimus,” said Dr. Yao.

As with METEOR, this trial is also ongoing, and like that investigation, an interim analysis of RADIANT-4 suggests an overall survival benefit for everolimus (HR=0.64; p=NS).

“The benefit was demonstrated early, with early separation of the curve at the two month time point and was durable, with curves separated for more than 18 months," Dr. Yao noted.

The next update on overall survival will be reported in 2016.

NETTER-1
 

Moving on from everolimus but staying with NETs, Philippe Ruszniewski, MD, Chief of Division of Gastroenterology and Pancreatology, Beaujon Hospital, Paris, reported on his use of the radio-therapeutic, 177Lu-DOTATATE (Lutathera) in patients with mid-gut NETs.

“NETs are a group of tumors originating in the neuroendocrine cells of many different organs,” said Dr. Ruszniewski. “These cancers are rare, but they are the second most common type of GI malignancy, and incidence is on the rise.” Indeed, the incidence of NET has grown by almost 500% since 1973.

The SOC for mid-gut NETs is front-line use of somatostatin analogues. Failing that, there are no approved treatment options.

Lutathera, administered as an IV, is a peptide receptor radionuclide therapy composed of lutetium chelated to a targeting peptide. The targets are somatostatin receptors which are overexpressed in 80% of NETs. Once bound by tumor cells, the drug is internalized and thereby causes radiation-induced DNA damage, followed by cell death.

For this phase III investigation, patients with advance mid-gut NET were randomized to Lutathera + Octreotide LAR (SOC), or SOC alone (N=230). 

Presenting an interim analysis of this study, Dr. Ruszniewski reported that the overall response rate was 19% for Lutathera vs 3% for SOC (p<0.0004). As for PFS, the median threshold had yet to be reached at the time of data analysis, but was 8.4 months for SOC alone (p<0.0001). Though not yet statistically significant, a numerical superiority for overall survival was also seen with Lutathera. “This appears to be a major advance in this patient population,” said Dr. Ruszniewski.   

Adverse events were reported as, “not a big issue,” though low grade thrombocytopenia and neutropenia were observed.

COMBI-v
 

This presentation was a two-year overall survival (OS) update of a phase III trial that has already reported its primary endpoint (https://obroncology.com/obrgreen/print/ESMO-Redux-All-Stars-and-Also-Rans). The present analysis included a further 11 months of data.

As revisited by Caroline Robert, MD, PhD, the COMBI-v study compared the doublet of dabrafenib/trametinib with vemurafenib monotherapy in patients with unresectable, or metastatic BRAF-mutation positive melanoma (1:1 randomization; N=704).

At two years, the OS for the doublet was 51% vs 38% for monotherapy, translating into a median survival of 25.6 months for the combination vs 18.0 months for vemurafenib alone (p<0.001).

“This is the longest overall survival reached in a randomized study in this patient population – the longest ever,” concluded Dr. Robert. She added that, in her opinion, the data supported the use of dabrafenib + trametinib as standard of care in this disease setting.

IMPRINT (Dud)
 

IMPRINT did not leave a favorable impression.

The phase III IMPRINT trial featured the drug IMA901, a vaccine cocktail with 10 different tumor-associated peptides that was administered with the immune system booster, GM-CSF, to a population of patients with advanced RCC currently receiving sunitinib (N=339).

In brief, the trial did not meet its endpoint of improved overall survival.

As stated by the study's authors: “Methods to significantly improve the magnitude and polarization of immune responses would need to be identified before further development of IMA901 in mRCC is indicated.”

And so it goes.

Next up is ASH 2015. See you there.
 

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